Genotype-driven NPC1L1 and PCSK9 inhibition and reduced risk of periodontitis.

Abstract

Epidemiological and pre-clinical studies suggest a chemoprotective role of lipid-lowering agents in periodontitis. We tested the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9) with periodontitis. Genetic variants in HMGCR, NCP1L1 and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N= 188,578) were used to proxy therapeutic inhibition of HMGCR, NPC1L1 and PCSK9. For these genetic variants, associations with periodontitis were obtained from GWAS of 17,353 cases and 28,210 controls in the GeneLifestyle Interactions in Dental Endpoints consortium. Generalized weighted least squares analysis accounted for linkage disequilibrium of genotypes to derive pooled estimates. While genetically proxied HMGCR inhibition equivalent to 1 mmol/L reduction in LDL was not associated with odds of periodontitis (odds ratio [OR]=0.92 [95% confidence interval [CI]: 0.73; 1.16]; p= .4905; false discovery rate [FDR]=0.4905), genetically proxied NPC1L1 (OR=0.53 [95% CI: 0.35; 0.81]; p= .0038; FDR=0.0077) and PCSK9 (OR=0.84 [95% CI: 0.74; 0.95]; p= .0051; FDR=0.0077) inhibition lowered the odds of periodontitis. Genetically proxied inhibition of NCP1L1 and PCSK9 was associated with lower odds of periodontitis.